| 1. |
- Qundos, Ulrika, 1983-
(författare)
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Antibody based plasma protein profiling
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is about protein profiling in serum and plasma using antibody suspension bead arrays for the analysis of biobanked samples and in the context of prostate cancer biomarker discovery. The influence of sample preparation methods on antibody based protein profiles were investigated (Papers I-III) and a prostate cancer candidate biomarker identified and verified (Papers III-V). Furthermore, a perspective on the research area affinity proteomics and its’ employment in biomarker discovery, for improved understanding and potentially improved disease diagnosis, is provided.Paper I presents the results of a comparative plasma and serum protein profiling study, with a targeted biomarker discovery approach in the context of metabolic syndrome. The study yielded a higher number of significant findings and a low experimental variability in blood samples prepared as plasma. Paper II investigated the effects from post-centrifugation delays at different temperatures prior sample storage of serum and plasma samples. Minor effects were found on the detected levels of more than 300 predicted or known plasma proteins. In Paper III, the detectability of proteins in plasma was explored by exposing samples to different pre-analytical heat treatments, prior target capture. Heat induced epitope retrieval was observed for approximately half of the targeted proteins, and resulted in the discovery of different candidate markers for prostate cancer. Several antibodies towards the prostate cancer candidate biomarker CNDP1 were generated, epitope mapped and evaluated in a bead based sandwich immunoassay, as presented in Papers IV and V. Furthermore, the developed sandwich immunoassay targeting multiple distinct CNDP1 epitopes in more than 1000 samples, confirmed the association of CNDP1 levels to aggres- sive prostate cancer and more specifically to prostate cancer patients with regional lymph node metastasis (Paper V).As an outcome of the present investigations and in parallel to studies within the Biobank profiling research group, valuable lessons from study design and multiplex antibody analysis of plasma within biomarker discovery to experimental, technical and biological verifications have been collected.
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| 2. |
- Nilsson, Jenny A. U., 1978-
(författare)
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On methods for estimating oceanic flow
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to estimate and possibly quantify ocean flow by utilizing conventional and novel observational methods as well as model results. Motionally induced voltages, from a cable-based observational system in the Baltic Sea, were analysed to determine their utility for ocean monitoring. The data set was examined as regards the influence of single- and multi-layer flow. Correlation analyses undertaken in the first study showed that the geoelectric installation is capable of providing good estimates of the net flow across the Visby-Västervik transect. The second study focused on possible effects of multi-layer flow on the signal. Comparisons were made with tidal-gauge geostrophic flow estimates, and a good agreement was found, except for a few brief winter periods characterized by significant discrepancies. The velocity fields from a three-dimensional model showed that these events coincided with strong surface and bottom currents, and hence the attenuated voltage signal was suggested as being caused by the non-uniform velocity distribution.The third study dealt with the deep-water flow through the Understen-Märket trench. Observational data indicated that this flow could be described by applying hydraulic theory. Since the passage is narrow compared to the internal Rossby radius of deformation, rotational effects could be neglected to lowest order. The theoretical predictions proved to agree well with the observational results.The final study examined the effects of the heat flux and the wind forcing on the circulation in Bahía de Concepción, Chile, where three field surveys were undertaken during the extended austral summer 2002. Hydrographic and current measurements were compared to local tidal-gauge records. Rough estimates of the barotropic and the baroclinic flow across the transect indicated an unusual vortex circulation during periods of weak wind forcing and strong surface heating; results which were corroborated by numerical simulations.
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| 3. |
- Engberg, Anna E., 1982-
(författare)
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Biomaterials and Hemocompatibility
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Biomaterials are commonly used in the medical clinic today; however, artificial materials can activate the cascade systems in the blood (complement-, coagulation-, contact- and fibrinolytic systems) as well as the platelets to various degrees. When an artificial surface comes in contact with blood, plasma proteins will be adsorbed to the surface within seconds. The composition of the layer of proteins differs between materials and is crucial for the hemocompatibility of the material.This thesis includes five projects.In Paper I the anticoagulants heparin and the thrombin inhibitor hirudin were evaluated in a whole blood model. Hirudin was found to be superior to low dose heparin since it did not affect the activation of the complement system nor the leukocytes. The most interesting observation was that expression of TF was seen on surface-attached monocytes in hirudin- treated blood but not heparin blood.In Paper II peptides from the streptococcal M-protein, which has affinity for the human complement inhibitor C4BP, were attached to a polymeric surface. When being exposed to blood the endogenous complement regulator was enriched at the surface of the material, via the M-peptides. With this new approach we created a self-regulatory surface, showing significant lowered material-induced complement activation.In Paper III apyrase, an enzyme which hydrolyzes nucleoside ATP and ADP, was immobilized on a polymer surface. Lower platelet activation and platelet-induced coagulation activation was seen for the apyrase-coated surface compared to control surfaces after exposure to whole human blood, due to the enzymes capability to degrade ADP released from activated platelets.In Paper IV and V we synthesized an array of polymeric materials which were characterized regarding physical-chemical properties, adsorption of plasma proteins, and hemocompatibility. The polymers showed widely heterogeneous protein adsorption. Furthermore, when the polymers were exposed to whole blood, two of the materials showed superior hemocompatibility (monitored as complement- and coagulation activation), compared to the reference poly(vinyl chloride).
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| 4. |
- Hertz, Erik, 1956-
(författare)
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Parabolic Synthesis
- 2011
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many consumer products, such as within the computer areas, computer graphics, digital signal processing, communication systems, robotics, navigation, astrophysics, fluid physics, etc. are searching for high computational performance as a consequence of increasingly more advanced algorithms in these applications. Until recently the down scaling of the hardware technology has been able to fulfill these higher demands from the more advanced algorithms with higher clock rates on the chips. This that the development of hardware technology performance has stagnated has moved the interest more over to implementation of algorithms in hardware. Especially within wireless communication the desire for higher transmission rates has increased the interest for algorithm implementation methodologies. The scope of this thesis is mainly on the developed methodology of parabolic synthesis. The parabolic synthesis methodology is a methodology for implementing approximations of unary functions in hardware. The methodology is described with the criteria's that have to be fulfilled to perform an approximation on a unary function. The hardware architecture of the methodology is described and to this a special hardware that performs the squaring operation. The outcome of the presented research is a novel methodology for implementing approximations of unary functions such as trigonometric functions, logarithmic functions, as well as square root and division functions etc. The architecture of the processing part automatically gives a high degree of parallelism. The methodology is founded on operations that are simple to implement in hardware such as addition, shifts, multiplication, contributes to that the implementation in hardware is simple to perform. The hardware architecture is characterized by a high degree of parallelism that gives a short critical path and fast computation. The structure of the methodology will also assure an area efficient hardware implementation.
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| 5. |
- Linnros, Evelina, 1990-
(författare)
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Essays on Fertility and Health
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Infertility Risk and Child MarriageThe high infertility rates observed in some developing countries may have broad societal impacts, for example by people marrying and having children at a young age to increase their chances of reaching their fertility target. I study the link between infertility risk and marriage timing using data from Madagascar. Specifically, I focus on how infertility risk affects the probability of child marriage, a practice associated with adverse outcomes for young brides and their children. I use spatial variation in exposure to the parasite schistosomiasis. The empirical strategy compares two strains of this parasite, similar in their transmission mechanisms and health impacts, except that one of the two strains causes infertility. In my data, exposure to this strain increases the probability that a woman is infertile by 40%. I find that exposure to the infertility-causing strain increases the probability of child marriage and early fertility by 22%.Maternal Health and Labor Market OutcomesWe study how severe injuries related to childbirth affect mothers' labor market outcomes. 1 in 20 first-time mothers who have a vaginal delivery suffer a severe birth tear, which can have long-lasting adverse impacts on their health and quality of life. Using a difference-in-differences design with a matched control group, we find that severe birth tears lead to a 6% higher earnings loss in the first five years after childbirth compared to the control group. The effect is larger for mothers from low SES backgrounds, while high SES mothers are found to seek more healthcare following their injury.Alcohol Availability, Prenatal Conditions and Midlife Mental Health We examine the long-term mental health effects of an 8.5-month policy experiment that led to a sharp and unexpected increase in alcohol availability, focusing on individuals exposed to the policy in utero. We use administrative healthcare and drug prescription records to identify individuals who have received treatment for a mental health disorder. Prenatal exposure to the policy had a large and persistent effect on mental health: the exposed cohort is 16% more likely to be treated for a mental disorder in midlife. The effect is largest for those exposed from the second trimester and is only partly explained by the lower earnings observed among exposed individuals.The Value of Monitoring for Disaster Prevention: The Desert LocustMonitoring systems are meant to detect early signs of potentially disastrous outbreaks of diseases and pests, in time for preventative action. These monitoring systems are costly, and identifying their economic value requires estimating damages from outbreaks in empirical settings where monitoring is neither uniform nor exogenous. We estimate the value of monitoring systems for desert locusts, known to devour entire agricultural fields. We leverage conflict and weather events in breeding areas to detect the effects of monitoring interruptions on swarm outbreaks. We then reconstruct the spatial patterns of locust migrations to propagate these effects on swarm outbreaks beyond breeding areas. Finally, we show that in-utero exposure to a swarm increases the probability of stunting by 16%. These estimates allow us to quantify the effects of a change in monitoring efforts on subsequent locust swarms and on human health.
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| 6. |
- Mohammad, Rezwan, 1975-
(författare)
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Some aspects of the Atlantic ocean circulation
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present thesis deals with the ocean circulation from two viewpoints: Pro primo, the dependence of the global thermohaline ocean circulation (THC) on the parameterization of the small-scale vertical mixing processes in the interior of the ocean, and, pro secundo, the dynamics of the circulation in the Nordic Seas. The THC is found be crucially dependent on the parameterization of the small-scale vertical mixing, two types of which have been compared: The commonly used constant diffusivity and a, physically more plausible, stability-dependent parameterization. For constant diffusivity the circulation weakens when the equator-to-pole surface density difference is decreased, consonant with commonly held prejudices. However, for stability-dependent diffusivity the circulation is enhanced. This conclusion has been reached using two investigative techniques, viz. a scale analysis as well as a numerical zonally-averaged and equatorially symmetric THC model. However, if asymmetric flows are considered, the dynamics become more complex to interpret. It has, nevertheless, been concluded that when the degree of asymmetry of the surface-density distribution is taken to be fixed, the response of the circulation to changes of the surface-density distribution corresponds to that from the symmetric investigation.The studies of the Nordic Seas are mainly based on satellite-altimetric data providing Sea-Level Anomalies (SLAs). These are utilized to estimate the seasonal cycle as well as the inter-annual variability of the depth-integrated flows. The seasonal cycle is examined using the winter-to-summer difference of the barotropic flow, with focus on the entire region as well as on two sections extending from a common point in the central Norwegian Sea to Svinøy on the Norwegian coast and to the Faroe Islands, respectively. The total barotropic transport is estimated to be around 10 Sv larger during winter than in summer, of which 8 Sv are associated with the barotropic re-circulation gyre in the interior of the Norwegian Sea, the remainder being linked to the Atlantic inflow across the Iceland-Scotland Ridge. The inter-annual variability of the circulation in the Nordic Seas is investigated on the basis of a theoretical analysis permitting independent calculation of the barotropic flow along closed isobaths using SLA data as well as wind data. The barotropic flow based on SLA data is found to co-vary with the flow estimated using wind data.
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| 7. |
- Nordqvist, Yvonne, 1975-
(författare)
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Development and Evaluation of a Denuder-Filter System Designed for Sampling Diisocyanate Aerosols
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There are many occupational environments in which isocyanates or PUR-products are used, produced or processed. During these operations there is always a risk of isocyanate exposure, which may lead to severe health problems. Isocyanates principally affect the respiratory system and they are the main cause of occupational asthma. The prevalence of asthma among exposed workers is generally 5-10%, according to most studies, but figures as high as 30% have been reported.The most commonly used isocyanates may occur in both vapour and particulate forms. Their physical state may affect both their deposition in the airways and their impact on health. Nevertheless, the occupational exposure limit for isocyanates applies to the total amount of isocyanates present, regardless of their physical state. Setting different exposure limits for vapour and particles would require the air sampling step to be capable of separating and independently measuring the phases. This is not straightforward, since every sampling method may be affected by a number of possible sampling artefacts. To minimize such biases, a profound knowledge of the sampling system and its behaviour is required.In this thesis a chemosorptive cylindrical denuder and filter, connected to a sampling pump, has been developed for personal exposure measurements of isocyanates. The model compounds for the investigation and evaluation were some of the most commonly used diisocyanates in industry: toluene diisocyanate (TDI), hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI) and methylene diphenyl diisocyanate (MDI). Using a combination of dimethylpolysiloxane (SE-30) and dibutylamine (DBA) as a chemosorptive coating on both the inner wall of the denuder tube and the filter, the derivatisation was shown to be fast enough for efficient collection of the isocyanates. The repeatability of the air measurements was high, with variabilities generally between 5-10% in the measured concentration range. 15-min samplings were performed of both vapour and aerosols of nm-size, from below the OEL (5ppbv) up to 235 ppbv, without exceeding the coating capacity or causing breakthrough due to chromatographic movement. At the applied airflow rates, between 50 and 500 ml/min, the breakthrough, i.e. the percentage of the TDI vapour that passes through the denuder tube ending up on the filter, was shown to be consistent with amounts predicted by the Gormley-Kennedy equation. For isocyanate aerosols, extensive gas-stripping was shown to occur inside the denuder tube at the lower end of the investigated flow range. This phenomenon was minimized when a flow rate between 300 and 500 ml/min was applied (Papers III-IV).The great advantage of a denuder sampler compared to wet methods, such as the commonly used impinger method, is its suitability for personal exposure measurements. Due to its small size and absence of solvent it is more convenient to carry during a work shift. Furthermore, the results in Paper II indicate that 8-hour denuder measurements can be performed without detectable breakthrough of the vapour phase. The derivatives formed during the sampling of isocyanates were shown to be stable in the samplers for several days after the measurements were finished, provided both the denuder tubes and filters were stored in the freezer and in solvent containing excess reagent. Furthermore, filters and tubes could be prepared at least 4 d prior to sampling, without loss of performance. This is highly relevant to the applicability of the method for field measurements.Both LC-ESI-MS (Paper II-IV) and LC-APCI-MS (Paper I) were used to determine the analytes in the air samples. The former method exhibited the lowest detection limit for the isocyanate-DBA derivatives. Using selected reaction monitoring (SRM) the obtained method detection limit for the investigated compounds was below 10 ng/m3.
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| 8. |
- Remnestål, Julia
(författare)
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Dementia Proteomics
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The term dementia encompass a number of conditions arising as a consequence of tissue degeneration in the brain. This degeneration is caused by molecular events occurring on a cellular level including inflammation, defective waste disposal and accumulation of insoluble proteins and peptides. Many of these molecular events are in turn also reflected in the composition of the cerebrospinal fluid (CSF) which circulates within and around the brain. This thesis summarise five studies conducted with the aim to explore and profile CSF proteins in the context of dementia and other neurodegenerative disorders. Protein profiles were obtained by so-called suspension bead arrays (SBAs), created by coupling antibodies to color-coded microspheres, allowing detection of more than 350 CSF proteins simultaneously. The majority of the explored proteins are referred to as brain-enriched, entailing that the corresponding genes are highly expressed in brain tissue in comparison to other tissues. In Paper I, the SBA technology was utilised to profile about 280 proteins in CSF from several neurodegenerative disorders, i.e. Alzheimer’s disease (AD), dementia with Lewy Bodies and Parkinson’s disease. Distinct differences in the CSF proteome were identified depending on site of collection (ventricular or lumbar) and time point (post mortem or ante mortem). Disease-associated profiles for the two synaptic proteins neuromodulin (GAP43) and neurogranin (NRGN) could be confirmed, in which both proteins displayed higher levels in AD compared to controls. High levels of the two proteins were furthermore observed in patients at preclinical stages of AD in two independent cohorts. To verify the identified protein profiles, parallel reaction monitoring (PRM) assays were developed for 17 proteins in Paper II, including GAP43. Eight proteins displayed concordance to data generated with SBAs and among these were GAP43, cholecystokinin, neurofilament medium chain (NF-M), leucine-rich alpha-2-glycoprotein and vascular cell adhesion protein 1. In Paper III, the SBA technology was again applied to characterise early dementia-related changes in the CSF proteome by comparing samples from individuals with mild cognitive impairment (MCI), controls and AD patients in two independent cohorts. The MCI individuals were moreover stratified based on CSF concentration of the core AD biomarkers Aβ42 and tau. The six proteins amphiphysin, aquaporin 4, cAMP regulated phosphoprotein 21, β-synuclein, GAP43 and NF-M did all show significant differences between sample groups in both cohorts. Further exploration of how the pathological processes preceding dementia affect the CSF proteome, was done by analysis of 104 brain-enriched proteins in CSF from asymptomatic 70 year-olds in Paper IV. Protein profiles were correlated to Aβ42, t-tau and p-tau CSF concentration, revealing a large number of proteins displaying significant correlations to tau levels. Upon dividing the asymptomatic individuals based on Aβ42 CSF pathology, some proteins showed significantly different associations in the two groups. Most of these proteins yielding interesting profiles, were plasma membrane proteins or proteins connected to synaptic vesicle transport. While AD is the most common form of dementia, accounting for more than 60 % of all cases worldwide, frontotemporal dementia (FTD) is the most frequently occurring form of young-onset dementia. In Paper V, CSF protein profiles were explored in the context of FTD. Patients with behavioural variant FTD and primary progressive aphasia, were compared to unaffected individuals with a high risk of developing FTD. Proteomic differences between patients with FTD and the unaffected individuals were observed already at a global level, and particularly for the six proteins NF-M, neurosecretory protein VGF, neuronal pentraxin receptor, prodynorphin, transmembrane protein 132D and tenascin-R. The disease-associated profiles identified in the presented studies provide a basis for future research within dementia proteomics. Whether the proteins identified will have the possibility to aid in clinical diagnosis, prognosis or characterisation of dementia, remains to be evaluated. Given the fortunate situation, especially in Sweden, with access to large and well characterised CSF collections, there are ample opportunities for future proteomic studies to elucidate the true potential of these proteins.
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